Quinoline derivatives as inhibitors of MEK enzymes

ABSTRACT

A compound of formula (I)                    
     or a pharmaceutically acceptable salt thereof; for use as a medicament wherein: 
     n is 0-1; 
     Y is selected from —NH—, —O—, —S—, or —NR 7 — where R 7  is alkyl of 1-6 carbon atoms 
     R 5  is chloro or bromo; 
     Y is selected from —NH—, —O—, —S—, or —NR 7 — where R 7  is alkyl of 1-6 carbon atoms 
     R 6  is a specified cyclic group which may be substituted by various specified substituents, 
     or R 6  is a group —R 8 —X—R 9  where 
     R 8  is selected from various cycloalkyl, pyridinyl, pyimidinyl, or phenyl ring; any of which may be optionally subsituted as described, 
     where X is selected from CH 2 , —NH—, —O—, —S—, CH 2  or —NR 5 — where R 5  is alkyl of 1-6 carbon atoms, and R 9  is a group (CH 2 ) m R 10  where m is 0, or an integer of from 1-3 and R 10  is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, 
     or R 10  is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally one or more substitutents; and R 1 , R 2 , R 3  and R 4  are each independently selected from hydrogen or various specified organic groups. Novel compounds are also described. The compounds are particularly useful in the inhibition of MEK enzymes.

This application is the National Phase of International ApplicationPCT/GB00/01707 filed May 3, 2000 which designated the U.S. and thatInternational Application was published under PCT Article 21(2) inEnglish.

The present invention relates to certain novel quinoline derivatives aswell as to their use as pharmaceuticals, in particular as inhibitors ofspecific kinase enzymes, in particular MEK enzymes. Further aspects ofthe invention include pharmaceutical compositions and methods oftreatment of proliferative disease such as cancer using said compounds.

Cancer is a disease in which cells grow and divide in an uncontrolledfashion. This uncontrolled growth arises from abnormalities in signaltransduction pathways that are used by normal cells to regulate cellgrowth and division in response to various signalling molecules. Normalcells do not proliferate unless stimulated to do so by specific signalmolecules located outside the cell derived from nearby cells or tissues.Growth factors bind to the cell membrane via specific receptors whichhave intrinsic enzyme activity. These receptors relay the growth signalto the cell nucleus via a series of signalling proteins. In cancer, anumber of defects in signal pathways are apparent. For example, cancercells may produce their own growth factors which bind to their cognatereceptors, resulting in an autocrine loop, or receptors may be mutatedor overexpressed leading to an increased, continuous signal toproliferate. In addition, negative regulators of cell growth may belost.

Oncogenes are cancer related genes which often encode abnormal versionsof signal pathway components, such receptor tyrosine kinases,serine-threonine kinasem or downstream signaling molecules such as theras genes, which code for closely related small guanine nucleotidebinding proteins which hydrolyse bound guanosine triphosphate (GTP) toguanosine diphosphate (GDP). Ras proteins are active in promoting cellgrowth and transformation when they are bound to GTP and inactive whenthey are bound to GDP. Transforming mutants of p21ras are defective intheir GTPase activity and hence remain in the active GTP bound state.The ras oncogene is known to play an integral role in certain cancers,and has been found to contribute to the formation of over 20% of allcases of human cancer.

When activated by ligand, cell surface receptors which are coupled tothe mitogenic response, such as growth factor receptors, initiate achain of reactions which leads to the activation of guanine nucleotideexchange activity on ras. When in its active GTP-bound state, a numberof proteins interact directly with ras at the plasma membrane resultingin signal transmission through several distinct pathways. The bestcharacterised effector protein is the product of the raf proto-oncogene.The interaction of raf and ras is a key regulatory step in the controlof cell proliferation. Ras-mediated activation of the rafserine-threonine kinase in turn activates the dual-specificity MEK (MEK1and MEK2), which is the immediate upstream activator of mitogenactivated protein kinase (MAPKs known as extracellular signal regulatedprotein kinases or ERK1 and ERK2). To date, no substrates of MEK otherthan MAPK have been identified, though recent reports indicate that MEKmay also be activated by other upstream signal proteins such as MEKkinase or MEKK1 and PKC. Activated MAPK translocates and accumulates inthe nucleus, where it can phosphorylate and activate transcriptionfactors such as Elk-1 and Sap1a, leading to the enhanced expression ofgenes such as that for c-fos.

The ras-dependent raf-MEK-MAPK cascade is one of the key signallingpathways responsible for transmitting and amplifying mitogenic signalsfrom cell surface to the nucleus resulting in changes in gene expressionand cell fate. This ubiquitous pathway appears essential for normal cellproliferation and constitutive activation of this pathway is sufficientto induce cellular transformation. Transforming mutants of p21ras areconstitutively active, resulting in raf, MEK and MAPK activity and celltransformation. Inhibition of MEK activity using either antisense raf, adominant negative MEK mutant or the selective inhibitor PD098059 havebeen shown to block the growth and morphological transformation ofras-transformed fibroblasts.

The mechanism of activation of raf, MEK and MAPK is throughphosphorylation on specific serene, threonine or tyrosine residues.Activated raf and other kinases phosphorylate MEK1 on S218 and S222 andMEK2 on S222 and S226. This results in MEK activation and subsequentphosphorylation and activation of ERK1 on T190 and Y192 and ERK2 on T183and Y185 by the dual specificity MEKs. Whilst MEK can be activated by anumber of protein kinases, and active MAPKs phosphorylate and activate anumber of substrate proteins including transcription factors and otherprotein kinases, MEKs appear specific and sole activators of MAPKs andcould act as a focal point for cross-cascade regulation. MEK1 and MEK2isoforms show unusual specificity and also contain a proline-rich insertbetween catalytic subdomains IX and X which is not present in any of theother known MEK family members. These differences between MEK and otherprotein kinases, together with the known role of MEK in proliferativesignalling suggest that it may be possible to discover and employselective MEK inhibitors as therapeutic agents for use in proliferativedisease.

WO 98/43960 discloses a range of 3-cyano quinoline compounds and theiruse in the treatment of cancer. Certain of the compounds aredemonstrated as being inhibitors of Epidermal Growth Factor ReceptorKinase, and to inhibit cancer cell growth. Other quinoline derivativeswhich inhibit the effect of growth factors such as VEGF are described inWO98/13350.

The conformations of certain diquinolinyl sulfides have been studied byNMR and reported by Wyszomirski et al in Phosphorus, Sulphur andSilicon, 1994, vol 95-96, pg 415-416. Methods of making specificquinoline derivatives are described by Atkins et al in Organic ProcessResearch and Development, 1997, vol 1, pg 185-197. The use of certainquinoline derivatives as gastric (H⁺/K⁺)—ATPase inhibitors and asfungicides are described by Ife et al in J Med Chem, 1992, vol 35, pg3413-3422 and in EP 326330 respectively.

This invention provides compounds which are inhibitors of the kinaseactivity of MEK and as a result, can produce therapeutically usefuleffects in the treatment of proliferative disease and in particularcancer.

According to the present invention there is provided a compound offormula (I)

or a pharmaceutically acceptable salt thereof; for use as a medicamentwherein:

n is 0-1;

Y is selected from —NH—, —O—, —S—, or —NR⁷— where R⁷ is alkyl of 1-6carbon atoms

R⁵ is chloro or bromo;

Y is selected from —NH—, —O—, —S—, or —NR⁷— where R⁷ is alkyl of 1-6carbon atoms

R⁶ is cycloalkyl of 3 to 7 carbon atoms, which may be optionallysubstituted with one or more alkyl of 1 to 6 carbon atom groups; or is apyridinyl, pyrimidinyl, or phenyl ring;

wherein the pyridinyl, pyrimidinyl, or phenyl ring may be substitutedwith one, two or three groups selected from the group consisting ofhalogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynylof 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms,halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms,hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7carbon atoms, carboalkyl of 2-7 carbon atoms, phenyl, benzoyl, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms,alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms,alkynoylamino of 3-8 carbon atoms, and benzoylamino; or two adjacentsubstitutents on said phenyl, pyridyl or pyrimidinyl ring may be joinedtogether to form a fused ring, which ring may be aromatic ornon-aromatic in character and which may contain further heteroatoms;

or R⁶ is a group —R⁸—X—R⁹ where

R⁸ is a divalent cycloalkyl of 3 to 7 carbon atoms, which may beoptionally further substituted with one or more alkyl of 1 to 6 carbonatom groups; or is a divalent pyridinyl, pyimidinyl, or phenyl ring;wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionallyfurther substituted with one or more groups selected from halogen, alkylof 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbonatoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethylof 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy,trifluoromethyl cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms,carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl,benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbonatoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbonatoms, and benzoylamino;

where X is selected from CH₂, —NH—, —O—, —S—, CH₂ or —NR⁵— where R⁵ isalkyl of 1-6 carbon atoms, and

R⁹ is a group (CH₂)_(m)R¹⁰ where m is 0, or an integer of from 1-3 andR¹⁰ is an optionally substituted aryl or optionally substitutedcycloalkyl ring of up to 10 carbon atoms, or R¹⁰ is a heterocyclic ringcontaining 1 or 2 oxygen atoms and optionally one or more substitutents;R¹, R², R³ and R⁴ are each independently selected from hydrogen,hydroxy, halogeno, cyano, nitro, trifluoromethyl, C₁₋₃alkyl, —NR¹¹R¹²(wherein R¹¹ and R¹², which may be the same or different, eachrepresents hydrogen or C₁₋₃alkyl), or a group R¹³—X¹—(CH₂)_(x) wherein xis 0 to 3, X¹ represents —O—, —CH₂—, —OCO—, carbonyl, —S—, —SO—, —SO₂—,—NR¹⁴CO—, —CONR¹⁵—, —SO₂NR¹⁶—, —NR¹⁷SO₂— or —NR¹⁸— (wherein R¹⁴, R¹⁵,R¹⁶, R¹⁷ and R¹⁸ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R¹³ is selected from one of the followingsixteen groups:

1) C₁₋₅alkyl which may be unsubstituted or which may be substituted withone or more groups selected from hydroxy, fluoro and amino;

2) C₁₋₅alkylX²COR¹⁹ (wherein X² represents —O— or —NR²⁰— (wherein R²⁰represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁹represents —NR²¹R²²— or —OR²³— (wherein R²¹, R²² and R²³ which may bethe same or different each represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl));

3) C₁₋₅alkylX³R²⁴ (wherein X³ represents —O—, —S—, —SO—, —SO₂—, —OCO—,—NR²⁵CO—, —CONR²⁶—, —SO₂NR²⁷—, —NR²⁸SO₂— or —NR²⁹— (wherein R²⁵, R²⁶,R²⁷, R²⁸ and R²⁹ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R²⁴ represents hydrogen, C₁₋₃alkyl,cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which C₁₋₃alkyl group may bear one or two substituents selected fromoxo, hydroxy, halogeno and C₁₋₄alkoxy and which cyclic group may bearone or two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);

4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R³⁰ (wherein X⁴ and X⁵ which may be the same ordifferent are each —O—, —S—, —SO—, —SO₂—, —NR³¹CO—, —CONR³²—, —SO₂NR³³—,—NR³⁴SO₂— or —NR³⁵— (wherein R³¹, R³², R³³, R³⁴ and R³⁵ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁰ represents hydrogen or C₁₋₃alkyl);

5) C₁₋₅alkylR³⁶ (wherein R³⁶ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which heterocyclic group may bear one or two substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl andC₁₋₄alkoxy);

6) (CH₂)_(q)X⁶R³⁷ (wherein q is an integer from 0 to 5, X⁶ represents adirect bond, —O—, —S—, —SO—, —SO₂—, —NR³⁸CO—, CONR³⁹—, —SO₂NR⁴⁰—,—NR⁴¹SO₂— or —NR⁴²— (wherein R³⁸, R³⁹, R⁴⁰, R⁴¹ and R⁴² eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is a phenyl group, a pyridone group or a 5 or 6 membered aromaticheterocyclic group with 1 to 3 heteroatoms selected from O, N and S,which phenyl, pyridone or aromatic heterocyclic group may carry up to 5substituents selected from hydroxy, halogeno, amino, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄hydroxyalkoxy, C₁₋₄aminoalkyl,C₁₋₄alkylamino, carboxy, cyano, —CONR⁴³R⁴⁴ and —NR⁴⁵COR⁴⁶ (wherein R⁴³,R⁴⁴, R⁴⁵ and R⁴⁶, which may be the same or different, each representshydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));

7) C₂₋₆alkenylR³⁶ (wherein R³⁶ is as defined hereinbefore);

8) C₂₋₆alkynylR³⁶ (wherein R³⁶ is as defined hereinbefore);

9) X⁷R⁴⁷ (wherein X⁷ is —SO₂—, —O— or —CONR⁴⁸R⁴⁹— (wherein R⁴⁸ and R⁴⁹,which may be the same or different, each represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁷ represents C₁₋₅alkyl which may beunsubstituted or which may be substituted with one or more groupsselected from hydroxy, fluoro and amino) with the provisos that when X⁷is —SO₂—, X¹ is —O—, when X⁷ is —O—, X¹ is carbonyl, when X⁷ is—CONR⁴⁸R⁴⁹—, X¹ is —O— or NR¹⁸ (wherein R⁴⁸, R⁴⁹ and R¹⁸ are as definedhereinbefore);

10) C₂₋₆alkenylR³⁷ (wherein R³⁷ is as defined hereinbefore);

11) C₂₋₆alkynylR³⁷ (wherein R³⁷ is as defined hereinbefore);

12) C₂₋₆alkenylX⁸R³⁷ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—,—NR⁵⁰CO—, —CONR⁵¹—, —SO₂NR⁵²—, —NR⁵³SO₂— or —NR⁵⁴— (wherein R⁵⁰, R⁵¹,R⁵², R⁵³ and R⁵⁴ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃ alkoxyC₁₋₃alkyl) and R³⁷ is as defined hereinbefore);

13) C₂₋₆alkynylX⁹R³⁷ (wherein X⁹ represents —O—, —S—, —SO—, —SO₂—,—NR⁵⁵CO—, —CONR⁵⁶—, —SO₂NR⁵⁷—, —NR⁵⁸SO₂— or —NR⁵⁹— (wherein R⁵⁵, R⁵⁶,R⁵⁷, R⁵⁸ and R⁵⁹ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³⁷ is as defined hereinbefore);

14) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁷ (wherein X¹⁰ represents —O—, —S—, —SO—,—SO₂—, —NR⁶⁰CO—, —CONR⁶¹—, —SO₂NR⁶²—, —NR⁶³SO₂— or —NR⁶⁴— (wherein R⁶⁰,R⁶¹, R⁶², R⁶³ and R⁶⁴ each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R³⁷ is as defined hereinbefore);

15) R³⁶ (wherein R³⁶ is as defined hereinbefore); and

16) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁶ (wherein X¹⁰ and R³⁶ are as definedhereinbefore).

In particular the invention provides a compound of formula (I) as shownabove or a pharmaceutically acceptable salt thereof; for use as amedicament wherein:

n is 0-1;

Y is selected from —NH—, —O—, —S—, or —NR⁷— where R⁷ is alkyl of 1-6carbon atoms

R⁵ is chloro or bromo;

Y is selected from —NH—, —O—, —S—, or —NR⁷— where R⁷ is alkyl of 1-6carbon atoms

R⁶ is cycloalkyl of 3 to 7 carbon atoms, which may be optionallysubstituted with one or more alkyl of 1 to 6 carbon atom groups; or is apyridinyl, pyrimidinyl, or phenyl ring;

wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionallymono- di-, or tri-substituted with a substituent selected from the groupconsisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbonatoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbonatoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethylof 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbonatoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl,thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms,dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino,alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms,alkynoylamino of3-8 carbon atoms, and benzoylamino;

or R⁶ is a group —R⁸—X—R⁹ where

R⁸ is a divalent cycloalkyl of 3 to 7 carbon atoms, which may beoptionally further substituted with one or more alkyl of 1 to 6 carbonatom groups; or is a divalent pyridinyl, pyimidinyl, or phenyl ring;wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionallyfurther substituted with one or more groups selected from halogen, alkylof 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbonatoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethylof 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy,trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms,carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl,benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbonatoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbonatoms, and benzoylamino;

where X is selected from —NH—, —O—, —S—, CH₂ or —NR^(a)— where R^(a) isalkyl of 1-6 carbon atoms, and

R⁹ is a group (CH₂)_(m)R¹⁰ where m is 0, or an integer of from 1-3 andR¹⁰ is an optionally substituted aryl or optionally substitutedcycloalkyl ring of up to 10 carbon atoms, or R¹⁰ is a heterocyclic ringcontaining 1 or 2 oxygen atoms and optionally one or more substitutents;

R¹, R², R³ and R⁴ are each independently selected from hydrogen,hydroxy, halogeno, cyano, nitro, trifluoromethyl, C₁₋₃alkyl, —NR¹¹R¹²(wherein R¹¹ and R¹², which may be the same or different, eachrepresents hydrogen or C₁₋₃alkyl), or a group R¹³—X¹—(CH₂)_(x) wherein xis 0 to 3, X¹ represents —O—, —CH₂—, —OCO—, carbonyl, —S—, —SO—, —SO₂—,—NR¹⁴CO—, —SO₂NR¹⁶—, —NR¹⁷SO₂— or —NR¹⁸— (wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷ andR¹⁸ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R¹³ is selected from one of the sixteen groupsdefined above.

Suitable pharmaceutically acceptable salts of compounds of formula (I)include acid addition salts such as methanesulfonate, fumarate,hydrochloride, hydrobromide, citrate, maleate and salts formed withphosphoric and sulphuric acid. A preferred pharmaceutically acceptablesalt is a hydrochloride salt.

The alkyl portion of the alkyl, alkoxy, alkanoyloxy, alkoxymethyl,alkanoyloxymethyl, alkylsuphinyl, alkylsulphonyl, alkylsulfonamido,carboalkoxy, carboalkyl, alkanoylamino aminoalkyl, alkylaminoalkyl,N,N-dicycloalkylaminoalkyl, hydroxyalkyl, and alkoxyalkyl substituentsinclude both straight chain as well as branched carbon chains. Thecycloalkyl portions of N-cycloalkyl-N-alkylaminoalkyl andN,N-dicycloalkylaminoalkyl substituents include both simple carbocyclesas well as carbocycles containing alkyl substituents. The alkenylportion of the alkenyl, alkenoyloxymethyl, alkenyloxy,alkenylsulfonamido, substituents include both straight chain as well asbranched carbon chains and one or more sites of unsaturation. Thealkynyl portion of the alkynyl, alkynoyloxymethyl, alkynylsulfonamido,alkynyloxy, substituents include both straight chain as well as branchedcarbon chains and one or more sites of unsaturation. Carboxy is definedas a —CO₂H radical. Carboalkoxy of 2-7 carbon atoms is defined as a—CO₂R″ radical, where R″ is an alkyl radical of 1-6 carbon atoms.Carboalkyl is defined as a —COR″ radical, where R″ is an alkyl radicalof 1-6 carbon atoms. Alkanoyloxy is defined as a —OCOR″ radical, whereR″ is an alkyl radical of 1-6 carbon atoms. Alkanoyloxymethyl is definedas R″CO₂CH₂— radical, where R″ is an alkyl radical of 1-6 carbon atoms.Alkoxymethyl is defined at R″OCH₂— radical, where R″ is an alkyl radicalof 1-6 carbon atoms. Alkyl sulphinyl is defined as R″SO— radical, whereR″ is an alkyl radical of 1-6 carbon atoms. Alkylsulphonyl is defined asR″SO₂— radical, where R″ is alkyl radical of 1-6 carbon atoms.Alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamido are defined asR″SO₂NH— radical, where R″ is an alkyl radical of 1-6 carbon atoms, analkenyl radical of 2-6 carbon atoms, or an alkynyl radical of 2-6 carbonatoms, respectively. N-alkylcarbamoyl is defined as R″NHCO— radical,where R″ is an alkyl radical of 1-6 carbon atoms. N,N-dialkylcarbamoylis defined as R″ R′NCO— radical, where R″ is an alkyl radical of 1-6carbon atoms, R′ is an alkyl radical of 1-6 carbon atoms and R′, and R″may be the same or different. When X is substituted, it is preferredthat it is mono-, di-, or tri-substituted, with monosubstituted beingmost preferred. It is preferred that of the substituents, R₁, R₂, R₃ andR₄ at least one is hydrogen and it is most preferred that two or threebe hydrogen. An azacycloalkyl-N-alkyl substituent refers to a monocyclicheterocycle that contains a nitrogen atom on which is substituted astraight or branched chain alkyl radical. A morpholino-N-alkylsubstituent is a morpholine ring substituted on the nitrogen atom with astraight or branch chain alkyl radical. A piperidino-N-alkyl substituentis a piperidine ring substituted on one of the nitrogen atoms with astraight or branch chain alkyl radical. A N-alkyl-piperazino-N-alkylsubstituent is a piperazine ring substituted on one of the nitrogenatoms with a straight or branched chain alkyl group and on the othernitrogen atom with a straight or branch chain alkyl radical.

When any group contains an alkyl portion, the alkyl portion containspreferably 1-6 carbon atoms, more preferably 1-4 carbon atoms,particularly methyl, ethyl, n-propyl iso-propyl, n-butyl, iso-butyl,sec-butyl or tert-butyl. When any group contains an alkenyl or alkynylportion, the alkenyl or alkynyl portion contains preferably 2-6 carbonatoms, more preferably 2-4 carbon atoms.

The term “aryl” used herein includes aromatic carbocyclic compounds, forexample of from 6 to 20 atoms such as phenyl or naphthyl. The term“heterocyclic” refers to ring structures suitably from 5 to 20 atoms insize, up to four of which are heteroatoms such as oxygen, sulphur andnitrogen. The ring structures may be monocyclic, bi- or tricyclic and bearomatic or non-aromatic in character including the possibility thatpart of a ring system has aromatic character whilst other part(s) donot.

The compounds of this invention may contain an asymmetric carbon; insuch cases, the compounds of this invention cover the racemate and theindividual R and S entantiomers, and in the case where more than oneasymmetric carbon exists, the individual diasteromers, their racematesand individual entantiomers.

Preferably Y is —NH—.

Preferably R⁵ is chloro.

Suitably R^(a) is phenyl, pyridyl or pyrimidinyl, and preferably phenylwhich are optionally substituted as defined above. Suitable substituentsinclude halo such as chloro or fluoro, hydroxy or benzoyl.

When two adjacent substitutents on said phenyl, pyridyl or pyrimidinylring are be joined together to form a fused ring, the ring is suitably a5 or 6 membered aromatic ring, and preferably a 5 membered ring whichincludes at least one heteroatom such as nitrogen. Particular examplesof groups R^(a) are indole, benzimidazole, or indazole.

In a preferred embodiment, the group R⁶ is a group —R⁸—X—R⁹ where R⁸, Xand R⁹ are as defined above. Suitably X is oxygen.

Preferably n is 0.

Examples of optional substituents for groups R¹⁰ include one or moregroups selected from hydroxy; halo; nitro; cyano; carboxy; C₁₋₆alkoxy;C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; C₂₋₆alkenyloxy; C₂₋₆alkynyloxy;C₃₋₆cycloalkyl; amino; mono- or di-C₁₋₆alkyl amino; heterocyclyloptionally substituted with C₁₋₄alkyl or oxo; C(O)R^(a), C(O)OR^(a),S(O)_(d)R^(a;) NR^(a)C(O)R^(b); C(O)NR^(a)S(O)_(d)R^(b),C(O)NR^(a)R^(b;); NR^(a)C(O)NR^(b)R^(c); NR^(a)S(O)_(d)R^(b) orN(S(O)_(d)R^(b))S(O)_(d)R^(c) where d is 0, 1 or 2 and R^(a), R^(b) andR^(c) are independently selected from hydrogen, C₁₋₆alkyl, aryl,C₃₋₆cycloalkyl or heterocylcyl, and wherein any alkyl, alkenyl oralkynyl group or moiety contained within the substituent one R¹⁰ maythemselves be optionally substituted with one or more groups selectedfrom hydroxy; cyano; nitro; halo; carboxy; carboalkoxy of 2-7 carbonatoms, C₃₋₆cycloalkyl, heterocyclyl optionally substituted withC₁₋₆alkyl or oxo; C(O)R^(d), C(O)OR^(d)NR^(d)R^(e), S(O)_(e)R^(d),NR^(d)C(O)R^(e); C(O)NR^(d)R^(e); NR^(d)C(O)NR^(e)R^(f);NR^(d)S(O)_(e)R^(e) where e is 0, 1 or 2 and R^(d), R^(e) and R^(f) areindependently selected from hydrogen or C₁₋₆alkyl optionally substitutedwith one or more groups selected from hydroxy; cyano; nitro; halo;carboxy; carboalkoxy of 2-7 carbon atoms, C₃₋₄cycloalkyl, heterocyclyloptionally substituted with C₁₋₆alkyl or oxo; C(O)R^(g),C(O)OR^(g)NR^(g)R^(h), S(O)_(e)R^(g), NR^(h)C(O)R^(g); C(O)NR^(g)R^(h);NR^(g)C(O)NR^(h)R^(i); NR^(g)S(O)_(e)R^(h) where e is as defined aboveand R^(g), R^(h) and R^(i) are independently selected from hydrogen orC₁₋₆alkyl. Alternatively, two substituents on adjacent atoms may bejoined to form the second ring of a bicyclic ring system wherein thesaid second ring is optionally substituted with one or more of thegroups listed above for R¹⁰ and optionally contains one or moreheteroatoms.

In some embodiments, the level of substitution on the group R¹⁰ is achain substituted with a complex substituent. Thus, for example, asubstituent may comprise an subsituted alkyl chain which is optionallyinterposed with heteroatoms such as groups of sub-formula (i)

—X^(a)—R⁷⁰—(X^(b)—R⁷¹)_(q)—(X^(c))_(s)—R⁷²  (i)

where X^(a), X^(b) and X^(c) are independently selected from any of thegroups listed above for X′,

R⁷⁰ and R⁷¹ are independently selected from C₁₋₄alkylene, C₂₋₄alkenyleneor C₂₋₄alkynylene groups any of which may be optionally substituted withhydroxy; cyano; nitro; halo; carboxy, carboalkoxy of 2-7 carbon atoms orC₃₋₄cycloalkyl;

R⁷² is hydrogen or an C₁₋₄alkyl, C₂₋₄ alkenyl or C₂₋₄alkynyl group anyof which may be optionally substituted with hydroxy; cyano; nitro; halo;carboxy or C₃₋₄cycloalkyl;

and q and s are independently 0 or 1.

Particular examples of groups R¹⁰ include phenyl or cycloalkyl of from3-8 and preferably of 6 carbon atoms which are substituted at theposition alpha with a alkoxy group, in particular methoxy.

When R¹⁰ is substituted phenyl or cycloalkyl, m is preferably 0.

Examples of heterocyclic rings R¹⁰ include 3-7 membered rings, up to twoof which may be oxygen atoms. Such groups include:

where each R⁶⁵ is independently selected from hydrogen or C₁₋₆alkyl andespecially methyl. In such compounds, m is suitably 1, 2 or 3.

Suitable further substitutents for R⁸ include those listed above forpyridyl, pyrimidinyl and phenyl groups R^(6.)

Thus a preferred sub-group of compounds of formula (I) are compounds offormula (II)

(II)

where R¹, R², R³, R⁴ and R⁵ are as defined above and R⁶⁶ is C₁₋₆ alkylin particular methyl and R⁶⁷ is selected from hydrogen, halogen, alkylof 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbonatoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethylof 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy,trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms,carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl,benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbonatoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbonatoms, and benzoylamino.

Preferably R⁶⁷ is hydrogen.

Examples of preferred groups for R¹, R², R³ and R⁴ are set out in WO98/13350. Preferably x is 0. Conveniently R¹³ is selected from one ofthe following sixteen groups:

1) C₁₋₅alkyl which may be unsubstituted or substituted with one or morefluorine atoms, or C₂₋₅alkyl which may be unsubstituted or substitutedwith one or more groups selected from hydroxy and amino;

2) C₂₋₃alkylX²COR¹⁹ (wherein X² is as defined hereinbefore and R¹⁹represents —NR²¹R²²— or —OR²³— (wherein R²¹, R²² and R²³ which may bethe same or different each represents hydrogen, C₁₋₂alkyl orC₁₋₂alkoxyethyl));

3) C₂₋₄alkylX³R²⁴ (wherein X³ is as defined hereinbefore and R²⁴represents hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 5 or 6membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N, which C₁₋₃alkyl group may bearone or two substituents selected from oxo, hydroxy, halogeno andC₁₋₃alkoxy and which cyclic group may bear one or two substituentsselected from oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl andC₁₋₃alkoxy);

4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R³⁰ (wherein X⁴ and X⁵ are as definedhereinbefore and R³⁰ represents hydrogen or C₁₋₃alkyl);

5) C₁₋₅alkylR⁷⁰ (wherein R⁷⁰ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which heterocyclic group is linked to C₁₋₅alkyl through a carbon atomand which heterocyclic group may bear one or two substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃hydroxyalkyl and C₁₋₃alkoxy)or C₂₋₅alkylR⁷¹ (wherein R⁷¹ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms of which one is N and the other isselected independently from O, S and N, which heterocyclic group islinked to C₂₋₅alkyl through a nitrogen atom and which heterocyclic groupmay bear one or two substituents selected from oxo, hydroxy, halogeno,C₁₋₃alkyl, C₁₋₃hydroxyalkyl and C₁₋₃alkoxy);

6) (CH₂)_(q)X⁶R³⁷ (wherein X⁶ is as defined hereinbefore; q is aninteger from 0 to 4 if X⁶ is a direct bond and q is 0, 2 or 3 if X⁶ isother than a direct bond; and R³⁷ is a phenyl group, a pyridone group ora 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatomsselected from O, N and S, of which preferably one is N, which phenylgroup, pyridone group or aromatic heterocyclic group may be substitutedas hereinbefore defined, advantageously substituted with up to 2substituents as hereinbefore defined, more preferably substituted withone substituent selected from the group of substituents as hereinbeforedefined);

7) C₄₋₅alkenylR⁷² (wherein R⁷² represents R⁷⁰ or R⁷¹ as definedhereinbefore);

8) C₄₋₅alkylR⁷² (wherein R⁷² represents R⁷⁰ or R⁷¹ as definedhereinbefore);

9) X⁷R⁴⁷ (wherein X⁷ is as defined hereinbefore and R⁴⁷ representsC₁₋₃alkyl which may be unsubstituted or which may be substituted withone or more groups selected from hydroxy, fluoro and amino);

10) C₃₋₅alkenylR³⁷ (wherein R³⁷ is as defined hereinbefore);

11) C₃₋₅alkynylR³⁷ (wherein R³⁷ is as defined hereinbefore);

12) C₄₋₅alkenylX⁸R³⁷ (wherein X⁸ and R³⁷ are as defined hereinbefore);

13) C₄₋₅alkynylX⁹R³⁰ (wherein X⁹ and R³⁰ are as defined hereinbefore);

14) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁷ (wherein X¹⁰ and R³⁷ are as definedhereinbefore);

15) R³⁶ (wherein R³⁶ is as defined hereinbefore); and

16) C₁₋₃alkylX¹¹C₁₋₃alkylR³⁶ (wherein X¹¹ and R³⁶ are as definedhereinbefore).

Advantageously R¹³ is selected from one of the following eleven groups:

1) C₁₋₄alkyl which may be unsubstituted or substituted with one or morefluorine atoms, or C₂₋₄alkyl which may be unsubstituted or substitutedwith one or two groups selected from hydroxy and amino;

2) C₂₋₃alkylX²COR¹⁹ (wherein X² is as defined hereinbefore and R¹⁹represents —NR²¹R²²— or —OR²³— (wherein R²¹, R²² and R²³ which may bethe same or different each represents hydrogen, C₁₋₂alkyl orC₁₋₂alkoxyethyl));

3) C₂₋₃alkylX³R²⁴ (wherein X³ is as defined hereinbefore and R²⁴ is agroup selected from C₁₋₃alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl andpiperidinyl which group is linked to X³ through a carbon atom and whichC₁₋₃alkyl group may bear one or two substituents selected from oxo,hydroxy, halogeno and C₁₋₃alkoxy and which cyclopentyl, cyclohexyl,pyrrolidinyl or piperidinyl group may carry one substituent selectedfrom oxo, hydroxy, halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl andC₁₋₂alkoxy);

4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R³⁰ (wherein X⁴ and X⁵ are as definedhereinbefore) and R³⁰ represents hydrogen or C₁₋₂alkyl);

5) C₁₋₄alkylR⁷⁰ (wherein R⁷⁰ is a group selected from pyrrolidinyl,piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl,1,3-dithiolan-2-yl and 1,3dithian-2-yl, which group is linked toC₁₋₄alkyl through a carbon atom and which group may carry one or twosubstituents selected from oxo, hydroxy, halogeno, C₁₋₂alkyl,C₁₋₂hydroxyalkyl and C₁₋₂alkoxy) or C₂₋₄alkylR⁷¹ (wherein R⁷¹ is a groupselected from morpholino, thiomorpholino, pyrrolidin-1-yl,piperazin-1-yl and piperidino which group may carry one or twosubstituents selected from oxo, hydroxy, halogeno, C₁₋₂alkyl,C₁₋₂hydroxyalkyl and C₁₋₂alkoxy); and

6) (CH₂)_(q)X⁶R³⁷ (wherein X⁶ is as defined hereinbefore; q is aninteger from 1 to 3 if X⁶ is a direct bond and q is 2 or 3 if X⁶ isother than a direct bond; and R³⁷ is a phenyl group, a pyridone group ora 5 or 6 membered aromatic heterocyclic group with 1 to 2 heteroatomsselected from O, N and S, of which preferably one is N, which phenylgroup, pyridone group or aromatic heterocyclic group may be substitutedas hereinbefore defined, preferably substituted with one substituentselected from hydroxy, halogeno, C₁₋₂alkyl, C₁₋₂alkoxy,C₁₋₂hydroxyalkyl, C₁₋₂hydroxyalkoxy, carboxy, cyano, —CONR⁴³R⁴⁴ and—NR⁴⁵COR⁴⁶ (wherein R⁴³, R⁴⁴, R⁴⁵ and R⁴⁶, which may be the same ordifferent, each represents hydrogen or C₁₋₂alkyl));

7) C₄₋₅alkenylR⁷¹ (wherein R⁷¹ is as defined hereinbefore);

8) C₄₋₅alkynylR⁷¹ (wherein R⁷¹ is as defined hereinbefore);

9) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁷ (wherein X¹⁰ and R³⁷ are as definedhereinbefore);

10) R³⁶ (wherein R³⁶ is as defined hereinbefore); and

11) C₁₋₃alkylX¹¹C₁₋₃ alkylR³⁶ (wherein X¹¹ and R³⁶ are as definedhereinbefore).

Preferably R¹³ is selected from one of the following nine groups:

1) C₁₋₃alkyl which may be unsubstituted or substituted with one or morefluorine atoms, or C₂₋₃alkyl which may be unsubstituted or substitutedwith one or two groups selected from hydroxy and amino;

2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,3-ureidopropyl 2(N,N-dimethylcarbamoyloxy)ethyl,3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl,3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,3-(carbamoyloxy)propyl;

3) C₂₋₃alkylX³R²⁴ (wherein X³ is as defined hereinbefore and R²⁴ is agroup selected from C₁₋₂alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl andpiperidinyl which group is linked to X³ through a carbon atom and whichC₁₋₂alkyl group may bear one or two substituents selected from oxo,hydroxy, halogeno and C₁₋₂alkoxy and which cyclopentyl, cyclohexyl,pyrrolidinyl or piperidinyl group may carry one substituent selectedfrom oxo, hydroxy, halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl andC₁₋₂alkoxy);

4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R³² (wherein X⁴ and X⁵ are as definedhereinbefore) and R³⁰ represents hydrogen or C₁₋₂alkyl);

5) C₁₋₂alkylR⁷⁰ (wherein R⁷⁰ is a group selected from pyrrolidinyl,piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl,1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked toC₁₋₂alkyl through a carbon atom and which group may carry onesubstituent selected from oxo, hydroxy, halogeno, C₁₋₂alkyl,C₁₋₂hydroxyalkyl and C₁₋₂alkoxy) or C₂₋₃alkylR⁵⁹ (wherein R⁵⁹ is a groupselected from morpholino, thiomorpholino, piperidino, piperazin-1-yl andpyrrolidin-1-yl which group may carry one or two substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl andC₁₋₂alkoxy);

6) (CH₂)_(q)X⁶R³⁷ (wherein X⁶ is as defined hereinbefore; q is aninteger from 1 to 3 if X⁶ is a direct bond and q is 2 or 3 if X⁶ isother than a direct bond; and R³⁷ is a group selected from phenyl, apyridone group, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl andpyridazinyl, preferably selected from phenyl, a pyridone group, pyridyl,imidazolyl, thiazolyl and triazolyl which group may be substituted withone substituent selected from hydroxy, halogeno, C₁₋₂alkyl, C₁₋₂alkoxy,C₁₋₂hydroxyalkyl, C₁₋₂hydroxyalkoxy, carboxy, cyano, —CONR⁴³R⁴⁴ and—NR⁴⁵COR⁴⁶ (wherein R⁴³, R⁴⁴, R⁴⁵ and R⁴⁶ are as defined hereinbefore);

7) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁷ (wherein X¹⁰ and R³⁷ are as definedhereinbefore);

8) R³⁶ (wherein R³⁶ is as defined hereinbefore); and

9) C₁₋₃alkylX¹¹C₁₋₃alkylR³⁶ (wherein X¹¹ and R³⁶ are as definedhereinbefore). More preferably R¹³ represents2-(methylthiazol-4-ylmethyl, 2-acetamidothiazol4-ylmethyl,1-methylimidazol-2-ylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl,2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N4-pyridyl)amino)ethyl, 2-(4-oxidomorpholino)ethyl,3-(4-oxidomorpholino)propyl, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl,3-(4-oxo-1,4-dihydro-1-pyridyl)propyl, methyl, ethyl, trifluoromethyl,2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,2-(N,N-dimethylsulphamoyl)ethyl, 2(N-methylsulphamoyl)ethyl,(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl,3-(2-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl,2-(1,2,4-triazol-1yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl,3-(1,2,4-triazol-1-yl)propyl, 3-(1,2,4-triazol-4-yl)propyl,2-(4-pyridyloxy)ethyl, 3-(4-pyridyloxy)propyl, 2-(4-pyridylamino)ethyl,3-(4-pyridylamino)propyl, 2-(2-(methylimidazol-1-yl)ethyl,3-(2-methylimidazol-1-yl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl,3-(5-methyl-1,2,4-triazol-1-yl)propyl, morpholino, N-methylpiperazinyl,piperazinyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl,2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, 2-methoxyethyl,3-methoxypropyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 3-(imidazol-1-yl)propyl,3-(1,2,3-triazol-1-yl)propyl, 3-(1,2,3-triazol-2-yl)propyl,2-thiomorpholinoethyl, 3-thiomorpholinopropyl,2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl,2-(2-(oxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl,3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl,3-(methylsulphonyl)propyl, 2-(methylsulphinyl)ethyl, benzyl,2-sulphamoylethyl or 2-(methylsulphonyl)ethyl.

Especially R¹³ represents methyl, ethyl, trifluoromethyl,2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl,2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl,3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl,2(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-(methylthiazol-4-ylmethyl,2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 3-(3-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl,2-(4-pyridylamino)ethyl, or 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl.

More especially R¹³ represents methyl, ethyl, trifluoromethyl,2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl,2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl,3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl,2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,2-acetamidothiazol4-ylmethyl, 1-methylimidazol-2-ylmethyl,2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1yl)ethyl,2-(1,2,4-triazol-4yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl,2-(4-pyridylamino)ethyl, or 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl.

In particular R¹ and R⁴ are suitably hydrogen.

Examples of preferred groups for R² include C₁₋₆ alkoxy or cyano, andpreferably C₁₋₆alkoxy such as methoxy.

The group R³ is suitably selected from hydrogen or C₁₋₆alkoxy such asmethoxy.

Preferably both R² and R³ are C₁₋₆ alkoxy and arc preferably methoxy.

Particular examples of compounds of formula (I) are listed in Table 1.

TABLE 1 NO. R¹ R² R³ R⁴ R⁵ R⁶ Y n Mass spec n.m.r. 1 H OCH₃ OCH₃ H Cl

NH 0 m/e 437 (M⁺ + H) (d-6-DMSO, d values) 3.7(s, 3H), 3.75(s, 3H),3.95(s, 3H), 6.85(m, 2H), 6.95(m, 1H), 7.05(m, 1H), 7.2(m, 4H), 7.45(s,1H), 7.5(s, 1H), 8.8(s, 1H), 10.15(broad, 1H). 2 H OCH₃ OCH₃ H Br

NH 0 m/e 483 (M⁺ + H) (d-6-DMSO, d values) 3.7(s, 3H), 3.75(s, 3H),3.9(s, 3H), 6.85(m, 2H), 7.05(m, 2H), 7.2(m, 4H), 7.4(s, 1H), 7.45(s,1H), 8.85(d, 1H), 10.0(b, 1H). 3 H OCH₃ OCH₃ H Cl

NH 0 m/e 333 (M⁺ + H) (d-6-DMSO, d values), 3.8(s, 3H), 3.95(s, 3H),7.3(m, 3H), 7.4(m, 1H), 7.55(s, 1H), 7.75(s, 1H), 8.85(s, 1H),10.22(broad, 1H). 4 H OCH₃ OCH₃ H Cl

NH 0 m/e 367 (M⁺ + H) (d-6-DMSO, d values), 3.9(s, 3H), 3.95(s, 3H),7.35(m, 2H), 7.55(s, 1H), 7.6(d, 1H), 7.85(s, 1H), 8.85(s, 1H),10.3(broad, 1H). 5 H OCH₃ OCH₃ H Cl

NH 0 m/e 383 (M⁺ + H) (d-6-DMSO, d values), 3.85(s, 3H), 3.95(s, 3H,7.05(dd, 1H), 7.35(d, 1H), 7.5(s 1H), 7.55(d 1H), 7.75(s, 1H), 8.9(s,1H), 10.32(broad, 1H). 6 H OCH₃ OCH₃ H Cl

NH 0 m/e 407 (M⁺ + H) (d-6-DMSO, d values), 3.75(s, 3H), 3.95(s, 3H),7.0(m, 4H), 7.1(m, 1H), 7.25(m, 2H), 7.4(m, 2H), 7.5(s, 1H), 7.6(s, 1H),8.8(s, 1H), 10.3(broad, 1H). 7 H OCH₃ OCH₃ H Br

NH 0 m/e 359 (M⁺ + H) (d-6-DMSO, d values), 3.7(s, 3H), 3.9(s, 3H),7.2(m, 3H), 7.4(m, 2), 7.48(s, 1H), 7.5(s, 1H), 8.9(s, 1H), 10.2(broad1H). 8 H OCH₃ OCH₃ H Br

NH 0 m/e 379 (M⁺ + H) (d-6-DMSO, d values), 3.7(s, 3H), 3.9(s, 3H),6.7(m, 1H), 7.0(m, 2H), 7.15(m, 1H), 7.35(s, 1H),7.37(s, 1H),8.35(broad, 1H), 8.6(s, 1H). 9 H OCH₃ OCH₃ H Br

NH 0 m/e 411 (M⁺ + H) (d-6-DMSO, d values), 3.9(s, 3H), 3.95(s, 3H),7.3(m, 2H), 7.5(s, 1H), 7.55(m, 1H), 7.825(s, 1H), 8.9(s, 1H),10.1(broad, 1H). 10 H OCH₃ OCH₃ H Br

NH 0 m/e 427 (M⁺ + H) (d-6-DMSO, d values), 3.85(s, 3H), 3.95(s, 3H),7.05(dd, 1H), 7.3(d, 1H), 7.5(s 1H), 7.55(d 1H), 7.75(s, 1H), 8.95(s,1H), 10.26(broad, 1H). 11 H OCH₃ OCH₃ H Br

NH 0 m/e 451 (M⁺ + H) (d-6-DMSO, d values), 3.75(s, 3H), 3.95(s, 3H),7.05(m, 4H), 7.15(m, 1H), 7.2(m, 2H), 7.4(m, 2H), 7.5(s, 1H), 7.55(s,1H), 8.85(s, 1H), 10.0(broad, 1H). 12 H CN H H Cl

NH 0 m/e 280 (M⁺ + H) (d-6-DMSO, d values) 7.15(m, 3H), 7.35(m, 2H),8.15(m, 1H), 8.25(d, 1H), 8.9(s, 1H), 8.95(s, 1H), 10.35(broad, 1H). 13H CN H H Cl

NH 0 m/e 298 (M⁺ + H) (d-6-DMSO, d values), 7.1(m, 3H), 7.25(m, 1H),8.02(m, 1H), 8.1(m, 1H), 8.75(s, 1H), 8.85(d, 1H), 9.1(broad, 1H). 14 HCN H H Cl

NH 0 m/e 332 (M⁺ + H) (d-6-DMSO, d values), 7.2(m, 2H), 7.5(m, 1H),8.15(m, 2H), 8.9(s, 1H), 9.0(s, 1H). 15 H CN H H Cl

NH 0 m/e 402 (M⁺ + H) (d-6-DMSO, d values), 3.7(s, 3H), 6.8(m, 2H),6.9(m, 4H), 7.15(m, 2H), 7.95(m, 1H), 8.05(m, 1H), 8.65(d, 1H), 8.75(s,1H), 9.05(broad, 1H). 16 H CN H H Cl

NH 0 m/e 296 (M⁺ + H) (d-6-DMSO, d values), 6.8(d, 2H), 7.05(d, 2H),8.1(dd, 1H), 8.2(d, 1H), 8.75(s, 1H), 8.9(s, 1H), 10.33(broad, 1H). 17 HCN H H Cl

NH 0 m/e 384 (M⁺ + H) (d-6-DMSO, d values), 7.0(d, 2H), 7.5(m, 2H).7.6(m, 1H), 7.7(m, 4H), 8.1(dd, 1H), 8.2(d, 1H), 8.8(d, 1H), 9.0(s, 1H),10.02(broad, 1H). 18 H CN H H Br

NH 0 m/e 324/326 (M⁺ + H) (d-6-DMSO, d values) 7.15(m, 3H), 7.35(m, 2H),8.2(m, 2H), 8.8(s, 1H), 9.05(s, 1H), 10.1(broad, 1H). 19 H CN H H Br

NH 0 m/e 342 (M⁺ + H) (d-6-DMSO, d values), 7.0(m, 1H), 7.1(m, 2H),7.2(m, 1H), 8.05(dd, 1H), 8.1(d, 1H), 8.8(d, 1H), 8.9(s, 1H), 9.0(broad,1H). 20 H CN H H Br

NH 0 m/e 376 (M⁺ + H) (d-6-DMSO, d values), 7.15(t, 1H), 7.25(dd, 1H),7.5(dd, 1H), 8.2(s, 2H), 9.05(s, 1H), 9.1(s, 1H). 21 H CN H H Br

NH 0 m/e 392 (M⁺ + H) (d-6-DMSO, d values), 6.9(dd, 1H), 7.15(d, 1H),7.5(d, 1H), 8.1(dd, 1H), 8.15(d, 1H), 8.85(d, 1H), 9.05(s, 1H),9.85(broad, 1H). 22 H CN H H Cl

NH 0 m/e 319 (M⁺ + H) (d-6-DMSO, d values), 6.45(m, 1H), 7.0(dd, 1H),7.4(m, 3H), 8.15(dd, 1H), 8.2(d, 1H), 8.65(s, 1H), 8.95(s, 1H),10.6(broad, 1H), 11.35(broad, 1H). 23 H CN H H Cl

NH 0 m/e 320 (M⁺ + H) (d-6-DMSO, d values), 6.8(m, 2H), 7.6(d, 1H),7.95(s, 1H), 8.02(dd, 1H), 8.15(d, 1H), 8.7(d, 1H), 8.85(s, 1H),9.25(broad, 1H), 12.7(broad, 1H). where * indicates the point ofattachment.

Certain compounds of formula (I) are novel and these provide a furtheraspect of the invention. In particular, the invention provides acompound of formula (IA) which comprises a compound of formula (I),provided that where R⁵ is bromo, R⁶ is other than phenyl, methylsubstituted phenyl or di-halo substituted phenyl.

Thus Examples of compounds of formula (IA) are compounds of formula (I)where R⁵ is chloro.

Other compounds of formula (IA) are compounds of formula (I) where R⁵ isbromo and R⁶ is cycloalkyl of 3 to 7 carbon atoms, which may beoptionally substituted with one or more alkyl of 1 to 6 carbon atomgroups; or is a pyridinyl pyrimidinyl, ring; wherein the pyridinyl,pyrimidinyl, or phenyl ring may be substituted with one, two or threegroups selected from the group consisting of halogen, alkyl of 1-6carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl,cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of2-7 carbon atoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbonatoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbonatoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbonatoms, and benzoylamino; or two adjacent substitutents on said, pyridylor pyrimidinyl ring may be joined together to form a fused ring, whichring may be aromatic or non-aromatic in character and which may containfurther heteroatoms, or R⁶ is a group —R⁵—X—R⁹ where R⁸, X and R⁹ are asdefined above.

Yet further compounds of formula (IA) are compounds of formula (I) whereR⁶ is phenyl which is substituted with one, two or three groups selectedfrom the group consisting of alkyl of 2-6 carbon atoms, alkenyl of 2-6carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro,carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbonatoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbon atoms,dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms,alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms,and benzoylamino; or two adjacent substitutents on said phenyl ring maybe joined together to form a fused ring, which ring may be aromatic ornon-aromatic in character and which may contain further heteroatoms

Preferred classes of compound of formula (IA) include those listed abovein respect of formula (I).

Compounds of formula (I) are suitably prepared by reacting a compound offormula (III)

(III)

where R^(1′), R^(2′), R^(3′), R^(4′) represent R¹, R², R³ and R⁴respectively as defined in relation to formula (I) or a precursorthereof, R⁵ is as defined in relation to formula (I), and Z′ is aleaving group, with a compound of formula (IV)

H—Y(CH₂)_(n)R^(6′)  (IV)

where Y, X, and n are as defined in relation to formula (I), and R^(6′)is a group R⁶ as defined in relation to formula (I) or a precursorthereof; and thereafter if necessary or desired converting precursorgroups R^(1′), R^(2′), R^(3′), R^(4′) and R^(6′) to groups of formulaR¹, R², R³, R⁴ and R⁶ respectively, or converting a group R¹, R², R³, R⁴and R⁶ to a different such group.

Suitable leaving groups for Z′ include halogen such as bromo or chloro,or a mesylate or tosylate group. In particular Z′ is chloro.

The reaction is suitably carried out in an organic solvent such as analcohol for example propanol, cyclohexanol, at elevated temperatures,for example of from 50 to 150° C., for example at about 105° C. or 110°C.

Conversion reactions in which precursor groups R^(1′), R^(2′), R^(3′),R^(4′) are converted to groups of formula R¹, R², R³ and R⁴respectively, or groups R¹, R², R³ and R⁴ are converted to differentsuch group can be carried out using conventional chemistry as describedin the literature. Particular precursor groups R^(1′), R^(2′), R^(3′),R^(4′) are groups of formula R^(13′)—X¹—(CH₂)_(x) wherein x and X¹ areas defined hereinafter, and R^(13′) is C₁₋₅alkyl which is substitutedwith halo other than fluoro, and in particular chloro or bromo. Thechloro group may readily be converted many other groups R¹³ as definedin relation to claim 1. Such compounds are novel and form a furtheraspect of the invention. They may have activity similar to that ofcompounds of formula (I) in their own right and therefore may be used inplace of a compound of formula (I).

Thus the invention further provides a compound of formula (IB)

(IB)

where Y, n, R⁵ and R⁶ are as defined above and at least one of R^(1″),R^(2″), R^(3″) or R^(4″) is a group R^(13′)—X¹—(CH₂)_(x) wherein X⁷ andx are as above and R^(13′) is alkyl substituted by chloro or bromo; andthe remainder are groups R¹, R², R³ and R⁴ respectively.

Similarly conversion reactions involving groups R^(6′) may be effectedusing conventional chemistry. For example substitutent groups on a groupR⁶ may be changed, for example by changing acids to esters or amidesetc.

A further example, to produce compounds of formula (I) where R⁶ is agroup —R⁸—X—R⁹ it to react a compound of formula (V)

(V)

where R^(1′), R^(2′), R^(3′), R^(4′) are as defined in relation toformula (III) R⁸, X, Y and n are as defined in relation to formula (I),with a compound of formula (VI)

R^(9′)—Z″  (VI)

where R^(9′) is a group R⁹ as defined in relation to formula (IV) or aprecursor thereof and Z″ is a leaving group;

and thereafter if necessary or desired converting precursor groupsR^(1′), R^(2′), R^(3′), R^(4′) and R^(9′) to groups of formula R¹, R²,R³, R⁴ and R⁹ respectively, or converting a group R¹, R², R³, R⁴ and R⁹to a different such group. Suitable leaving groups for Z″ includehalogen such a bromo or chloro, or a mesylate or tosylate group.Conversion reactions are as described above.

The reaction is suitably carried out in an organic solvent such as DMFat elevated temperatures, for example of from 40 to 120° C., for exampleat about 80° C.

Preferably however, R¹, R², R³, R^(4′), and R⁶ are groups R¹, R², R³, R⁴and R⁶ respectively and so no subsequent processing is required.

Certain compounds of formula (III) are disclosed in WO98/13350 andothers can be prepared from known compounds by analogous methods. Forexample, they are suitably prepared by reacting a compound of formula(V)

(V)

where R¹, R², R³, R⁴ and R⁵ are as defined in relation to formula (I),with a compound of formula (VI)

Z′—R²⁰  (VI)

where Z′ is as defined above and R²⁰ is a further leaving group such assulphonylchloride. A particular example of a compound of formula (VI) isthionyl chloride.

The reaction is suitably effected in an organic solvent such asdimethylformamide, at elevated temperatures for example of from 50 to150° C., and conveniently at the reflux temperature of the solvent.

Compounds of formula (V) may be prepared by chlorination or brominationof a compound of formula (VII)

(VII)

where R¹, R², R³ and R⁴ are as defined in relation to formula (I).

Halogenation can be effected using known halogenating agents such asN-halosuccinimides. The reaction is suitably effected in an organicsolvent such as carbon tetrachloride. It may advantageously be carriedout in the presence of a radical initiator such asazobisisobutyronitrile. Elevated temperatures of from 40 to 76° C. aresuitably employed. Where R⁵ is bromine, the reaction can also beeffected using bromine in aqueous solution in the presence of a basesuch as sodium hydroxide. A suitable temperature for such a reactionwould be in the range of from 20 to 25° C.

Compounds of formula (VII) are either known compounds (see for exampleWO99/00372 and WO9847873, or they can be prepared from known compoundsby conventional methods. Compounds of formula (IV) are also either knowncompounds (see for example Rev. Chim. (Bucharest (1988), 39(6), 477-82,DD110651:74.01.05) or they can be prepared from known compounds byconventional methods.

Compounds of the invention are useful in the inhibition of MEK enzymeactivity and can be used in the treatment of proliferative disease. Theywill suitably be in the form of a pharmaceutical composition, incombination with a pharmaceutically acceptable carrier. Suchcompositions form a further aspect of the invention.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal track, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxyethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedure well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30μ or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on Formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent to compounded with an appropriate andconvenient amount of excipients which may vary from about 5 to about 98percent by weight of the total composition. Dosage unit forms willgenerally contain about 1 mg to about 500 mg of an active ingredient.For further information on Routes of Administration and Dosage Regimesthe reader is referred to Chapter 25.3 in Volume 5 of ComprehensiveMedicinal Chemistry (Corwin Hansch; Chairman of Editorial Board),Pergamon Press 1990.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine. As mentioned above, compounds of the Formula I are useful intreating diseases or medical conditions which are due alone or in partto the effects of MEK enzymes.

In using a compound of the Formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used. Oral administration is howeverpreferred.

In a further aspect, the invention provides a method of treatingproliferative disease by administering a compound of formula (I) asdescribed above, or a pharmaceutical composition as described above.

Yet a further aspect of the invention provides the use of a compound offormula (I) as defined above, in the preparation of a medicament for usein the inhibition of MEK enzyme activity and in particular for thetreatment of proliferative disease such as cancer.

The invention will now be particularly described by way of Example.

EXAMPLE 1

Preparation of Compound 1 in Table 1

Step 1

N-chlorosuccinimide (1.8 g) and azobisisobutyronitrile (0.1 g) wereadded to a suspension of 6,7-dimethoxy-4-quinolone (2.05 g) in carbontetrachloride (100 ml). The mixture was stirred and heated to reflux for6 hours. The mixture was filtered. The solid was washed with water andthen dried. There was thus obtained 3-chloro-6,7-dimethoxy-4-quinolone(1.6 g, 66%).

Mass Spectrum m/e 240 (M⁺+H).

NMR Spectrum (d-6-DMSO, d values) 3.85 (s, 6H), 7.0 (s, 1H), 7.4 (s,1H), 8.2 (d, 1H).

Step 2

A mixture of the product of step 1 (1.6 g), thionyl chloride (25 ml) andDMF (3 drops) was stirred and heated to reflux for 5 hours. The thionylchloride was evaporated. The residue was treated with toluene which wasthen evaporated. This procedure was repeated. The residue was thentriturated with diethyl ether and then filtered. There was thus obtained3,4-dichloro-6,7-dimethoxyquinoline (1.65 g, 95%).

NMR Spectrum (CDCl₃, d values) 4.15 (s, 3H), 4.2 (s, 3H), 7.5 (s, 1H),8.2 (s, 1H), 8.8 (s, 1H).

Step 3

A mixture of 3,4-dichloro-6,7-dimethoxyquinoline (258 mg) and4-(2-(oxyphenoxy)-aniline (243 mg) in 1-propanol (15 ml) was stirred andheated at 100° C. for 18 hours. The mixture was cooled to ambienttemperature and then filtered. The crystals were washed with a smallvolume of 1-propanol and then dried to give4-(2-methoxyphenoxy)-anilino-3-chloro-6,7-dimethoxyquinoline (Compound 1in Table 1) (243 mg, 51%).

EXAMPLE 2

By an analogous procedure to that described in Example 1 but using analternative aniline, the following compounds were prepared.

Compound No 3 in Table 1—(from 2-fluoroaniline),

Compound No 4 in Table 1—(from 4-chloro-2-fluoro-aniline),

Compound No 5 in Table 1—(from 3,4-dichloroaniline),

Compound No 6 in Table 1—(from 4-phenoxyaniline).

EXAMPLE 3

Preparation of Compound 2 in Table 1

Step 1

N-bromosuccinimide (4.9 g) and azobisisobutyronitrile (0.2 g) were addedto a suspension of 6,7-dimethoxy-4-quinolone (4.1 g) in carbontetrachloride (200 ml). The mixture was stirred and heated to reflux for6 hours. The mixture was filtered. The solid was suspended in water andthen filtered and then dried. There was thus obtained3-bromo-6,7-dimethoxy-4-quinolone (3.2 g, 56%).

Mass Spectrum m/e 284/286 (M⁺+H).

NMR Spectrum (d-6-DMSO, d values) 3.8 (s, 3H), 3.85 (s, 3H), 7.0 (s,1H), 7.4 (s, 1H), 8.2 (d, 1H)

Step 2

A mixture of the product obtained in Step 1 (3.2 g), thionyl chloride(50 ml) and DMF (5 drops) was stirred and heated to reflux for 2 hours.The thionyl chloride was evaporated. The residue was treated withtoluene which was then evaporated. This procedure was repeated. Therewas thus obtained crude 3-bromo-4-chloro-6,7-dimethoxyquinoline (3.8g,).

NMR Spectrum (d-6-DMSO, d values) 3.9 (s, 6H), 7.4 (s, 1H), 7.45 (s,1H), 8.8 (s, 1H).

Step 3

A mixture of 3-bromo-4-chloro-6,7-dimethoxyquinoline (302 mg) and4-(2-methoxyphenoxy)-aniline (236 mg) in cyclohexanol (5 ml) was stirredand heated at 130° C. for 24 hours. The mixture was cooled to ambienttemperature and then filtered. The crystals were washed first withmethanol and then with diethyl ether and then dried to give4-(2-methoxyphenoxy)-anilino-3-bromo-6,7-dimethoxyquinoline (Compound 2)(180 mg, 37%).

EXAMPLE 4

By an analogous procedure to that described for Example 3 but using analternative aniline, the following compounds were prepared. Compound No.7 in Table 1—(from aniline), Compound No. 8 in Table 1—(from2-fluoroaniline), Compound No. 9 in Table 1—(from4-chloro-2-fluoro-aniline), Compound No. 10 in Table 1—(from3,4-dichloroaniline), Compound No. 11 in Table 1 —(from4-phenoxyaniline).

EXAMPLE 5

Preparation of Compound No 12 in Table 1

Step 1

Sodium hypochlorite solution (10% chlorine, 7.5 ml) was added dropwiseto a suspension of 6-cyano-4-quinolone (1.7 g) in sodium hydroxidesolution (2 molar, 15 ml). The mixture was stirred and cooled in ice tokeep the temperature <25° C. The mixture was left to stand for 18 hoursand then a further quantity of sodium hypochlorite solution (10%chlorine, 3 ml) was added dropwise. Water (25 ml) was added to themixture. The mixture was filtered and the filtrate acidified with aceticacid. The solid which precipitated was collected by filtration andwashed with water. There was thus obtained 3-chloro-6-cyano-4-quinolone(1.25 g, 61%).

Mass Spectrum m/e 205 (M⁺+H).

NMR Spectrum (d-6-DMSO, d values) 7.7 (d, 1H), 8.0 (m, 1H), 8.5 (m, 2H).

Step 2

A mixture of the product obtained in Step 1 (1.2 g), thionyl chloride(20 ml) and DMF (2 drops) was stirred and heated to reflux for 18 hours.The thionyl chloride was evaporated. The residue was treated withtoluene which was then evaporated. There was thus obtained crude3,4-dichloro-6-cyanoquinoline (1.3 g).

NMR Spectrum (d-6-DMSO, d values) 8.15 (m, 1H), 8.25 (d, 1H), 8.75 (m,1H), 9.15 (s, 1H).

Step 3

A mixture of 3,4-dichloro-6-cyanoquinoline (230 mg) and aniline (112 mg)in 1-propanol (5 ml) was stirred and heated at 100° C. for 24 hours. Themixture was cooled to ambient temperature. The product crystallised fromthe solution and was collected by filtration and washed with 1-propanol.There was thus obtained 4-anilino-3-chloro-6-cyanoquinoline (102 mg,36%)

EXAMPLE 6

By an analogous procedure to that described for Example 5 but using analternative aniline, the following compounds were prepared:

Compound No 13 in Table 1—(from 2-fluoroaniline),

Compound No 14 in Table 1 (from 4-chloro-2-fluoro-aniline),

Compound No 15 in Table 1(from 4-(2-(oxyphenoxy)-aniline).

Compound No 16 in Table 1 (from 4-hydroxyaniline),

Compound No. 17 in Table 1 (from 4-benzoylaniline).

Compound No. 22 in Table 1 (from 5-aminoindole),

Compound No 23 in Table 1 (from 6-aminoindazole).

EXAMPLE 7

Preparation of Compound No 18 in Table 1

Step 1

A solution of bromine was prepared by dissolving bromine (16 g) in water(100 ml) containing potassium bromide (30 g). This solution containingbromine (54 ml) was added dropwise to a suspension of6-cyano-4-quinolone (5.1 g) in sodium hydroxide solution (2 molar, 60ml). The mixture was stirred and cooled in ice to keep the temperatureat about 20° C. The mixture was left to stir for 4 hours and then afurther quantity of the bromine solution (15 ml) was added dropwise withthe temperature kept below 25° C. The mixture was stirred for a further1 hour and was then filtered. There was thus obtained3-bromo-6-cyano-4-quinolone (5.85 g, 78%).

Mass Spectrum m/e 249/251 (M⁺+H).

NMR Spectrum (d-6-DMSO, d values) 7.7 (d, 1H), 7.95 (m, 1H), 8.45 (d,1H), 8.55 (s, 1H).

Step 2

A mixture of the product of step 1 (5.8 g), thionyl chloride (100 ml)and DMF (10 drops) was stirred and heated at 90° C. for 18 hours. Thethionyl chloride was evaporated. The residue was treated with toluenewhich was then evaporated. There was thus obtained crude3-bromo-4-chloro-6-cyanoquinoline (6.58 g).

NMR Spectrum (d-6-DMSO, d values) 8.2 (d, 1H), 8.25 (s, 1H), 8.75 (s,1H), 9.2 (s, 1H).

Step 3

A mixture of 3-bromo-4-chloro-6-cyanoquinoline (267 mg) and aniline (186mg) in 1,4-dioxane (15 ml) was stirred and heated in a heater at 120° C.for 22 hours. The mixture was cooled to ambient temperature. The1,4-dioxane was evaporated. The residue was treated with dichloromethane(5 ml) tetramethyl guanidine (0.125 ml) and then purified by columnchromatography using initially dichloromethane thenmethanol/dichloromethane mixtures as eluent. The product was dissolvedin ethanol. The solution was acidified to pH 1-2 by addition of asolution of hydrogen chloride in diethyl ether (1.0 molar) and theproduct isolated by filtration. There was thus obtained4-anilino-3-bromo-6-cyanoquinoline(104 mg, 28%).

EXAMPLE 8

By an analogous procedure to that described for example 7 but using analternative aniline, the following compounds were prepared.

Compound 19 in Table 1 (from 2-fluoroaniline),

Compound 20 in Table 1 (from 4-chloro-2-fluoro-aniline),

Compound 21 in Table 1 (from 3,4-dichloroaniline),

Biological Results

Assay for Inhibitors of the MAP Kinase Pathway

To evaluate inhibitors of the MAPK pathway a coupled assay was carriedout which measures phosphorylation of serine/threonine residues presentin the substrate in the presence or absence of inhibitor. Recombinantglutathione S-transferase fusion protein containing human p45MEK1(GST-MEK) was activated by c-raf (Sf9 insect cell lysate from triplebaculoviral infection with c-raf/ras/lck) and used for the assay. ActiveGST-MEK was first used to activate a recombinant glutathioneS-transferase fusion protein containing p44MAP kinase (GST-MAPK) in thepresence of ATP and Mg²⁺ for 60min at room temperature in the presenceor absence of potential inhibitors. The activated GST-MAPK was thenincubated with myelin basic protein (MBP) as substrate for 10 min atroom temperature in the presence of ATP, Mg²⁺ and ³³P-ATP. The reactionwas stopped by addition of 20% v/v phosphoric acid. Incorporation of ³³Pinto the myelin basic protein was determined by capture of the substrateon a filter mat, washing and counting using scintillation methods. Theextent of inhibition was determined by comparison with untreatedcontrols.

The final assay solution contained 10 mM Tris, pH 7.5, 0.05 mM EGTA,8.33 μM [γ³³P]ATP, 8.33 mM Mg(OAc)₂, 0.5 mM sodium orthovanadate, 0.05%w/v BSA, 6.5 ng GST-MEK, 1 μg GST-MAPK and 16.5 μg MBP in a reactionvolume of 60 βl.

Compounds tested of the present invention had IC₅₀ results typicallyless than 20 μM. For example, Compound no 5 of Example 2 gave an IC₅₀ of1.53 μM.

In vitro MAP Kinase Assay

To determine whether compounds were inhibiting GST-MEK or GST-MAPK, adirect assay of MAPK activity was employed. GST-MAPK was activated by aconstitutively active GST-MEK fusion protein containing two pointmutations (S217E, S221E) and used for the assay in the presence andabsence of potential inhibitors. The activated GST-MAPK was incubatedwith substrate (MBP) for 60 min at room temperature in the presence ofATP, Mg²⁺ and ³³P-ATP. The reaction was stopped by addition of 20% v/vphosphoric acid. Incorporation of ³³P into the myelin basic protein wasdetermined by capture of the substrate on a filter mat, washing andcounting using scintillation methods.

The final assay solution contained 12 mM Tris, pH 7.5, 0.06 mM EGTA, 30μM [γ³³P]ATP, 10 mM Mg(OAc)₂, 0.6 mM sodium orthovanadate, 0.06% w/vBSA, 28 ng GST-MAPK and 16.5 μg MBP in a reaction volume of 60 μl .

Compounds of the invention showed activity in this screen.

Cell Proliferation Assays

Cells were seeded into multi-well plates at 20 000-40 000 cells/ml ingrowth medium containing 5% FCS and incubated overnight at 37° C. Thecompounds were prepared in fresh medium at an appropriate concentrationand added to the wells containing the cells. These were then incubatedfor a further 72 hours. Cells were then either removed from the wells byincubating with trypsin/EDTA and counted using a Coulter counter, ortreated with KIT/PMS in PBSA and optical densities read at 45 nM.Compounds tested of the present invention had IC₅₀ results typicallyless than 30 μM. Compound No 1 of Example 1 gave an IC50 of 3.4 μM inHT29 human colon tumour cells.

What is claimed is:
 1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof; wherein: n is 0-1; Y is—NH—; R⁵ is chloro or bromo; R⁶ is cycloalkyl of 3 to 7 carbon atoms,which may be optionally substituted with one or more alkyl of 1 to 6carbon atom groups; or is a pyridinyl, pyrimidinyl, or phenyl ring;wherein the pyridinyl, pyrimidinyl, or phenyl ring may be substitutedwith one, two or three groups selected from the group consisting ofhalogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynylof 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms,halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms,hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7carbon atoms, carboalkyl of 2-7 carbon atoms, phenyl, benzoyl, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms,alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms,alkynoylamino of 3-8 carbon atoms, and benzoylamino; or two adjacentsubstitutents on said phenyl, pyridyl or pyrimidinyl ring may be joinedtogether as a 5-membered heterocyclic ring having one or two nitrogenatoms, to form a fused ring; or R⁶ is a group —R⁸—X—R⁹ where R⁸ is adivalent cycloalkyl of 3 to 7 carbon atoms, which may be optionallyfurther substituted with one or more alkyl of 1 to 6 carbon atom groups;or is a divalent pyridinyl, pyimidinyl, or phenyl ring; wherein thepyridinyl, pyrimidinyl, or phenyl ring may be optionally furthersubstituted with one or more groups selected from halogen, alkyl of 1-6carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl,cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms,phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms,alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms,and benzoylamino; where X is selected from CH₂, —NH—, —O—, —S—, CH₂ or—NR⁵— where R⁵ is alkyl of 1-6 carbon atoms, and R⁹ is a group(CH₂)_(m)R¹⁰ where m is 0, or an integer of from 1-3 and R¹⁰ is anoptionally substituted aryl or optionally substituted cycloalkyl ring ofup to 10 carbon atoms, or R¹⁰ is a heterocyclic ring containing 1 or 2oxygen atoms and optionally one or more substitutents; R¹, R², R³ and R⁴are each independently selected from hydrogen, hydroxy, halogeno, cyano,nitro, trifluoromethyl, C₁₋₃alkyl, —NR¹¹R¹² (wherein R¹¹ R¹², which maybe the same or different, each represents hydrogen or C₁₋₃alkyl), or agroup R¹³—X¹—(CH₂)_(x) wherein x is 0 to 3, X¹ represents —O—, —CH₂—,—OCO—, carbonyl, —S—, —SO—, —SO₂—, —NR¹⁴CO—, —CONR¹⁵—, —SO₂NR¹⁶—,—NR¹⁷SO₂— or —NR¹⁸— (wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR¹³ is selected from one of the following sixteen groups: 1) C₁₋₅alkylwhich may be unsubstituted or which may be substituted with one or moregroups selected from hydroxy, fluoro and amino; 2) C₁₋₅alkylX²COR¹⁹(wherein X² represents —O— or NR²⁰— (wherein R²⁰ represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁹ represents —NR²¹R²²— or —OR²³—(wherein R²¹, R²² and R²³ which may be the same or different eachrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 3)C₁₋₅alkylX³R²⁴ (wherein X³ represents —O—, —S—, —SOH—, —SO₂—, —OCO—,—NR²⁵CO—, —CONR²⁶—, —SO₂NR²⁷—, —NR²⁸SO₂— or —NR²⁹— (wherein R²⁵, R²⁶,R²⁷, R²⁸ and R²⁹ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R²⁴ represents hydrogen, C₁₋₃alkyl,cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which C₁₋₃alkyl group may bear one or two substituents selected fromoxo, hydroxy, halogeno and C₁₋₄alkoxy and which cyclic group may bearone or two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R³⁰ (whereinX⁴ and X⁵ which may be the same or different are each —O—, —S—, —SO—,—SO₂—, —NR³¹CO—, —CONR³²—, —SO₂NR³³—, —NR³⁴SO₂— or —NR³⁵— (wherein R³¹,R³², R³³, R³⁴ and R³⁵ each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R³⁰ represents hydrogen or C₁₋₃alkyl); 5)C₁₋₅alkylR³⁶ (wherein R³⁶ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which heterocyclic group may bear one or two substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl andC₁₋₄alkoxy); 6) (CH₂)_(q)X⁶R³⁷ (wherein q is an integer from 0 to 5, X⁶represents a direct bond, —O—, —S—, —SO—, —SO₂—, —NR³⁸CO—, —CONR³⁹—,—SO₂NR⁴⁰—, —NR⁴¹SO₂— or —NR⁴²— (wherein R³⁸, R³⁹, R⁴⁰, R⁴¹ and R⁴² eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is a phenyl group, a pyridone group or a 5 or 6 membered aromaticheterocyclic group with 1 to 3 heteroatoms selected from O, N and S,which phenyl, pyridone or aromatic heterocyclic group may carry up to 5substituents selected from hydroxy, halogeno, amino, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄hydroxyalkoxy, C₁₋₄aminoalkyl,C₁₋₄alkylamino, carboxy, cyano, —CONR⁴³R⁴⁴ and —NR⁴⁵COR⁴⁶ (wherein R⁴³,R⁴⁴, R⁴⁵ and R⁴⁶, which may be the same or different, each representshydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 7) C₂₋₆alkenylR³⁶ (whereinR³⁶ is as defined hereinbefore); 8) C₂₋₆alkynylR³⁶ (wherein R³⁶ is asdefined hereinbefore); 9) X⁷R⁴⁷ (wherein X⁷ is —SO₂—, —O— or —CONR⁴⁸R⁴⁹—(wherein R⁴⁸ and R⁴⁹, which may be the same or different, eachrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁷represents C₁₋₅alkyl which may be unsubstituted or which may besubstituted with one or more groups selected from hydroxy, fluoro andamino) with the provisos that when X⁷ is —SO₂—, X¹ is —O—, when X⁷ is—O—, X¹ is carbonyl, when X⁷ is —CONR⁴⁸R⁴⁹—, X¹ is —O— or NR¹⁸ (whereinR⁴⁸, R⁴⁹ and R¹⁸ are as defined hereinbefore); 10) C₂₋₆alkenylR³⁷(wherein R³⁷ is as defined hereinbefore); 11) C₂₋₆alkynylR³⁷ (whereinR³⁷ is as defined hereinbefore); 12) C₂₋₆alkenylX⁸R³⁷ (wherein X⁸represents —O—, —S—, —SO—, —SO₂—, —NR⁵⁰CO—, —CONR⁵¹—, —SO₂NR⁵²—,—NR⁵³SO₂— or —NR⁵⁴— (wherein R⁵⁰, R⁵¹, R⁵², R⁵³ and R⁵⁴ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is as defined hereinbefore); 13) C₂₋₆alkynylX⁹R³⁷ (wherein X⁹represents —O—, —S—, —SO—, —SO₂—, —NR⁵⁵CO—, —CONR⁵⁶—, —SO₂NR⁵⁷—,—NR⁵⁸SO₂— or —NR⁵⁹— (wherein R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸ and R⁵⁹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is as defined hereinbefore); 14) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁷ (whereinX¹⁰ represents —O—, —S—, —SO—, —SO₂—, —NR⁶⁰CO—, —CONR⁶¹—, —SO₂NR⁶²—,—NR⁶³SO₂— or —NR⁶⁴— (wherein R⁶⁰, R⁶¹, R⁶², R⁶³ and R⁶⁴ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is as defined hereinbefore); 15) R³⁶ (wherein R³⁶ is as definedhereinbefore); and 16) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁶ (wherein X¹⁰ and R³⁶ areas defined hereinbefore), with the proviso that when R⁵ is bromo, R⁶ isother than unsubstituted phenyl, methyl substituted phenyl or di-halosubstituted phenyl.
 2. A compound according to claim 1 wherein R⁶ is agroup —R⁸—X—R⁹ where R⁸, X and R⁹ are as defined therein.
 3. A compoundof formula (II)

or a pharmaceutically acceptable salt thereof wherein: R¹, R², R³, R⁴are each independently selected from hydrogen, hydroxy, halogeno, cyano,nitro, trifluoromethyl, C₁₋₃alkyl, —NR¹¹R¹² (wherein R¹¹ and R¹², whichmay be the same or different, each represents hydrogen or C₁₋₃alkyl), ora group R¹³—X¹—(CH₂)_(x) wherein x is 0 to 3, X^(l) represents —O—,—CH₂—, —OCO—, carbonyl, —S—, —SO—, —SO₂—, —NR¹⁴CO—, —CONR¹⁵—, —SO₂NR¹⁶—,—NR¹⁷SO₂— or —NR¹⁸— (wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR¹³ is selected from one of the following sixteen groups: 1) C₁₋₅alkylwhich may be unsubstituted or which may be substituted with one or moregroups selected from hydroxy, fluoro and amino; 2) C₁₋₅alkylX²COR¹⁹(wherein X² represents —O— or —NR²⁰— (wherein R²⁰ represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁹ represents —NR²¹R²²— or —OR²³—(wherein R²¹, R²² and R²³ which may be the same or different eachrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 3)C₁₋₅alkylX³R²⁴ (wherein X³ represents —O—, —S—, —SO—, —SO₂—, —OCO—,—NR²⁵CO—, —CONR²⁶—, —SO₂NR²⁷—, —NR²⁸SO₂— or —NR²⁹— (wherein R²⁵, R²⁶,R²⁷, R²⁸ and R²⁹ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R²⁴ represents hydrogen, C₁₋₃alkyl,cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which C₁₋₃alkyl group may bear one or two substituents selected fromoxo, hydroxy, halogeno and C₁₋₄alkoxy and which cyclic group may bearone or two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R³⁰ (whereinX⁴ and X⁵ which may be the same or different are each —O—, —S—, —SO—,—SO₂—, —NR³CO—, —CONR³²—, —SO₂NR³³—, —NR³⁴SO₂— or —NR³⁵—(wherein R³¹,R³², R³³, R³⁴ and R³⁵ each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R³⁰ represents hydrogen or C₁₋₃alkyl); 5)C₁₋₅alkylR³⁶ (wherein R³⁶ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which heterocyclic group may bear one or two substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl andC₁₋₄alkoxy); 6) (CH₂)_(q)X⁶R³⁷ (wherein q is an integer from 0 to 5, X⁶represents a direct bond, —O—, —S—, —SO—, —SO₂—, —NR³⁸CO—, —CONR³⁹—,—SO₂NR⁴⁰—, —NR⁴¹SO₂— or —NR⁴²— (wherein R³⁸, R³⁹, R⁴⁰, R⁴¹ and R⁴² eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is a phenyl group, a pyridone group or a 5 or 6 membered aromaticheterocyclic group with 1 to 3 heteroatoms selected from O, N and S,which phenyl, pyridone or aromatic heterocyclic group may carry up to 5substituents selected from hydroxy, halogeno, amino, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄hydroxyalkoxy, C₁₋₄aminoalkyl,C₁₋₄alkylamino, carboxy, cyano, —CONR⁴³R⁴⁴ and —NR⁴⁵COR⁴⁶ (wherein R⁴³,R⁴⁴, R⁴⁵ and R⁴⁶, which may be the same or different, each representshydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 7) C₂₋₆alkenylR³⁶ (whereinR³⁶ is as defined hereinbefore); 8) C₂₋₆alkynylR³⁶ (wherein R³⁶ is asdefined hereinbefore); 9) X⁷R⁴⁷ (wherein X⁷ is —SO₂—, —O— or —CONR⁴⁸R⁴⁹—(wherein R⁴⁸ and R⁴⁹, which may be the same or different, eachrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁷represents C₁₋₅alkyl which may be unsubstituted or which may besubstituted with one or more groups selected from hydroxy, fluoro andamino) with the provisos that when X⁷ is —SO₂—, X¹ is —O—, when X⁷ is—O—, X¹ is carbonyl, when X⁷ is —CONR⁴⁸R⁴⁹—, X¹ is —O— or NR¹⁸ (whereinR⁴⁸, R⁴⁹ and R¹⁸ are as defined hereinbefore); 10) C₂₋₆alkenylR³⁷(wherein R³⁷ is as defined hereinbefore); 11) C₂₋₆alkynylR³⁷ (whereinR³⁷ is as defined hereinbefore); 12) C₂₋₆alkenylX⁸R³⁷ (wherein X⁸represents —O—, —S—, —SO—, —SO₂—, —NR⁵⁰CO—, —CONR⁵¹—, —SO₂NR⁵²—,—NR⁵³SO₂— or —NR⁵⁴— (wherein R⁵⁰, R⁵¹, R⁵², R⁵³ and R⁵⁴ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is as defined hereinbefore); 13) C₂₋₆alkynylX⁹R³⁷ (wherein X⁹represents —O—, —S—, —SO—, —SO₂—, —NR⁵⁵CO—, —CONR⁵⁶—, —SO₂NR⁵⁷—,—NR⁵⁸SO₂— or —NR⁵⁹— (wherein R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸ and R⁵⁹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is as defined hereinbefore); 14) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁷ (whereinX¹⁰ represents —O—, —S—, —SO—, —SO₂—, —NR⁶⁰CO—, —CONR⁶¹—, —SO₂NR⁶²—,—NR⁶³SO₂— or —NR⁶⁴ (wherein R⁶⁰, R⁶¹, R⁶², R⁶³ and R⁶⁴ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is as defined hereinbefore); 15) R³⁶ (wherein R³⁶ is as definedhereinbefore); and 16) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁶ (wherein X¹⁰ and R³⁶ areas defined hereinbefore); R⁵ is chloro or bromo; R⁶⁶ is C₁₋₆ alkyl andR⁶⁷ is selected from hydrogen, halogen, alkyl of 1-6 carbon atoms,alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido,hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbonatoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbonatoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms,phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms,alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms,and benzoylamino.
 4. A compound of formula (IB)

wherein: n is 0-1; Y is selected from —NH—; R⁵ is chloro or bromo; R⁶ iscycloalkyl of 3 to 7 carbon atoms, which may be optionally substitutedwith one or more alkyl of 1 to 6 carbon atom groups; or is a pyridinyl,pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, orphenyl ring may be substituted with one, two or three groups selectedfrom the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenylof 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro,carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbonatoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbon atoms,dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms,alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms,and benzoylamino; or two adjacent substitutents on said phenyl, pyridylor pyrimidinyl ring may be joined together as a 5-membered heterocyclicring having one or two nitrogen atoms, to form a fused ring; or R⁶ is agroup —R⁸—X—R⁹ where R⁸ is a divalent cycloalkyl of 3 to 7 carbon atoms,which may be optionally further substituted with one or more alkyl of 1to 6 carbon atom groups; or is a divalent pyridinyl, pyimidinyl, orphenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may beoptionally further substituted with one or more groups selected fromhalogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynylof 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms,halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms,hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl,thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms,dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino,alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms,alkynoylamino of 3-8 carbon atoms, and benzoylamino; where X is selectedfrom CH₂, —NH—, —O—, —S—, CH₂ or —NR⁵— where R⁵ is alkyl of 1-6 carbonatoms, and R⁹ is a group (CH₂)_(m)R¹⁰ where m is 0, or an integer offrom 1-3 and R¹⁰ is an optionally substituted aryl or optionallysubstituted cycloalkyl ring of up to 10 carbon atoms, or R¹⁰ is aheterocyclic ring containing 1 or 2 oxygen atoms and optionally one ormore substitutents; at least one of R^(1″), R^(2″), R^(3″) or R^(4″) isa group R^(13′)—X¹—(CH₂)_(x) wherein x is 0 to 3, X¹ represents —O—,—CH₂—, —OCO—, carbonyl, —S—, —SO—, —SO₂—, —NR¹⁴CO—, —CONR¹⁵—, —SO₂NR¹⁶—,—NR¹⁷SO₂— or —NR¹⁸— (wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl),and R^(13′) is alkyl substituted by chloro or bromo; and the remainderof groups R^(1″), R^(2″), R^(3″) or R^(4″) are each independentlyselected from hydrogen, hydroxy, halogeno, cyano, nitro,trifluoromethyl, C₁₋₃alkyl, —NR¹¹R¹² (wherein R¹¹ and R¹², which may bethe same or different, each represents hydrogen or C₁₋₃alkyl), or agroup R¹³—X¹—(CH₂)_(x) wherein x is 0 to 3, X¹ represents —O—, —CH₂—,—OCO—, carbonyl, —S—, —SO—, —SO₂—, —NR¹⁴CO—, —CONR¹⁵—, —SO₂NR¹⁶—,—NR¹⁷SO₂— or —NR¹⁸— (wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR¹³ is selected from one of the following sixteen groups: 1) C₁₋₅alkylwhich may be unsubstituted or which may be substituted with one or moregroups selected from hydroxy, fluoro and amino; 2) C₁₋₅alkylX²COR¹⁹(wherein X² represents —O— or —NR²⁰— (wherein R²⁰ represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁹ represents —NR²¹R²²— or—OR²³—(wherein R²¹, R²² and R²³ which may be the same or different eachrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 3)C₁₋₅alkylX³R²⁴ (wherein X³ represents —O—, —S—, —SO—, —SO₂—, —OCO—,—NR²⁵CO—, —CONR²⁶—, —SO₂NR²⁷—, —NR²⁸SO₂— or —NR²⁹— (wherein R²⁵, R²⁶,R²⁷ , R⁸² and R²⁹ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R²⁴ represents hydrogen, C₁₋₃alkyl,cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which C₁₋₃alkyl group may bear one or two substituents selected fromoxo, hydroxy, halogeno and C₁₋₄alkoxy and which cyclic group may bearone or two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R³⁰ (whereinX⁴ and X⁵ which may be the same or different are each —O—, —S—, —SO—,—SO₂—, —NR³¹CO—, —CONR³²—, —SO₂NR³³—, —NR³⁴SO₂— or —NR³⁵— (wherein R³¹,R³², R³³, R³⁴ and R³⁵ each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R³⁰ represents hydrogen or C₁₋₃alkyl); 5)C₁₋₅alkylR³⁶ (wherein R³⁶ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which heterocyclic group may bear one or two substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl andC₁₋₄alkoxy); 6) (CH₂)_(q)X⁶R³⁷ (wherein q is an integer from 0 to 5, X⁶represents a direct bond, —O—, —S—, —SO—, —SO₂—, —NR³⁸CO—, —CONR³⁹—,—SO₂NR⁴⁰—, —NR⁴¹SO₂— or —NR⁴²— (wherein R³⁸, R³⁹, R⁴⁰, R⁴¹ and R⁴² eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is a phenyl group, a pyridone group or a 5 or 6 membered aromaticheterocyclic group with 1 to 3 heteroatoms selected from O, N and S,which phenyl, pyridone or aromatic heterocyclic group may carry up to 5substituents selected from hydroxy, halogeno, amino, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄hydroxyalkoxy, C₁₋₄aminoalkyl,C₁₋₄alkylamino, carboxy, cyano, —CONR⁴³R⁴⁴ and —NR⁴⁵COR⁴⁶ (wherein R⁴³,R⁴⁴, R⁴⁵ and R⁴⁶, which may be the same or different, each representshydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 7) C₂₋₆alkenylR³⁶ (whereinR³⁶ is as defined hereinbefore); 8) C₂₋₆alkynylR³⁶ (wherein R³⁶ is asdefined hereinbefore); 9) X⁷R⁴⁷ (wherein X⁷ is —SO₂—, —O— or —CONR⁴⁸R⁴⁹—(wherein R⁴⁸ and R⁴⁹, which may be the same or different, eachrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁷represents C₁₋₅alkyl which may be unsubstituted or which may besubstituted with one or more groups selected from hydroxy, fluoro andamino) with the provisos that when X⁷ is —SO₂—, X¹ is —O—, when X⁷ is—O—, X¹ is carbonyl, when X⁷ is —CONR⁴⁸R⁴⁹—, X¹ is —O— or NR¹⁸ (whereinR⁴⁸, R⁴⁹ and R¹⁸ are as defined hereinbefore); 10) C₂₋₆alkenylR³⁷(wherein R³⁷ is as defined hereinbefore); 11) C₂₋₆alkynylR³⁷ (whereinR³⁷ is as defined hereinbefore); 12) C₂₋₆alkenylX⁸R³⁷ (wherein X⁸represents —O—, —S—, —SO—, —SO₂—, —NR⁵⁰CO—, —CONR⁵¹—, —SO₂NR⁵²—,—NR⁵³SO₂— or —NR⁵⁴— (wherein R⁵⁰, R⁵¹, R⁵², R⁵³ and R⁵⁴ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is as defined hereinbefore); 13) C₂₋₆alkynylX⁹R³⁷ (wherein X⁹represents —O—, —S—, —SO—, —SO₂—, —NR⁵⁵CO—, —CONR⁵⁶—, —SO₂NR⁵⁷—,—NR⁵⁸SO₂— or —NR⁵⁹— (wherein R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸ and R⁵⁹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR₃₇ is as defined hereinbefore); 14) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁷ (whereinX¹⁰ represents —O—, —S—, —SO—, —SO₂—, —NR⁶⁰CO—, —CONR⁶¹—, —SO₂NR⁶²—,—NR⁶³SO₂— or —NR⁶⁴— (wherein R⁶⁰ , R⁶¹, R⁶², R⁶³ and R⁶⁴ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is as defined hereinbefore); 15) R³⁶ (wherein R³⁶ is as definedhereinbefore); and 16) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁶ (wherein X¹⁰ and R³⁶ areas defined hereinbefore).
 5. A process for preparing a compound offormula (IA) as defined in claim 1, which process comprises reacting acompound of formula (III)

where R^(1′), R^(2′), R^(3′), R^(4′) represent R¹, R², R³ and R⁴respectively as defined in claim 1 or a precursor thereof, R⁵ is asdefined in claim 1, and Z′ is a leaving group, with a compound offormula (IV) H—Y(CH₂)_(n)R^(6′)  (IV) where Y, X, and n are as definedin claim 1, and R^(6′) is a group R⁶ as defined in claim 1 or aprecursor thereof; and thereafter if necessary or desired convertingprecursor groups R^(1′), R^(2′), R^(3′), R^(4′) and R^(6′) to groups offormula R¹, R², R³, R⁴ and R⁶ respectively, or converting a group R¹,R², R³, R⁴ and R⁶ to a different such group.
 6. A compound of formula(I)

or a pharmaceutically acceptable salt thereof wherein: n is 0-1; Y isselected from —NH—; R⁵ is chloro or bromo; R⁶ is cycloalkyl of 3 to 7carbon atoms, which may be optionally substituted with one or more alkylof 1 to 6 carbon atom groups; or is a pyridinyl, pyrimidinyl, or phenylring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may beoptionally mono- di-, or tri-substituted with a substituent selectedfrom the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenylof 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro,carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbonatoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylaminoof 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino,benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8carbon atoms, alkynoylamino of 3-8 carbon atoms, and benzoylamino; or R⁶is a group —R⁸—X—R⁹ where R⁸ is a divalent cycloalkyl of 3 to 7 carbonatoms, which may be optionally further substituted with one or morealkyl of 1 to 6 carbon atom groups; or is a divalent pyridinyl,pyimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl, orphenyl ring may be optionally further substituted with one or moregroups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro,carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbonatoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylaminoof 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino,benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8carbon atoms, alkynoylamino of 3-8 carbon atoms, and benzoylamino; whereX is selected from —NH—, —O—, —S—, CH₂ or —NR^(a)— where R^(a) is alkylof 1-6 carbon atoms, and R⁹ is a group (CH₂)_(m)R¹⁰ where m is 0, or aninteger of from 1-3 and R¹⁰ is an optionally substituted aryl oroptionally substituted cycloalkyl ring of up to 10 carbon atoms, or R¹⁰is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally oneor more substitutents; R¹, R², R³ and R⁴ are each independently selectedfrom hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl,C₁₋₃alkyl, —NR¹¹R¹² (wherein R¹¹ ¹ and R¹², which may be the same ordifferent, each represents hydrogen or C₁₋₃alkyl), or a groupR¹³—X¹—(CH₂)_(x) wherein x is 0 to 3, X¹ represents —O—, —CH₂—, —OCO—,carbonyl, —S—, —SO—, —SO₂—, —NR¹⁴CO—, —SO₂NR¹⁶—, —NR¹⁷SO₂— or —NR¹⁸—(wherein R¹⁴, R¹⁶, R¹⁷ and R¹⁸ each independently represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC2-3alkyl) and R¹³ is selected from one of thefollowing sixteen groups: 1) C₁₋₅alkyl which may be unsubstituted orwhich may be substituted with one or more groups selected from hydroxy,fluoro and amino; 2) C₁₋₅alkylX²COR¹⁹ (wherein X² represents —O— or—NR²⁰— (wherein R²⁰ represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R¹⁹ represents —NR²¹R²²— or —OR²³— (whereinR²¹, R²² and R²³ which may be the same or different each representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 3) C₁₋₅alkylX³R²⁴ (whereinX³ represents —O—, —S—, —SO—, —SO₂—, —OCO—, —NR²⁵CO—, —CONR²⁶—,—SO₂NR²⁷—, —NR²⁸SO₂— or —NR²⁹— (wherein R²⁵, R²⁶, R²⁷, R²⁸ and R²⁹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR²⁴ represents hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 5 or 6membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N, which C₁₋₃alkyl group may bearone or two substituents selected from oxo, hydroxy, halogeno andC₁₋₄alkoxy and which cyclic group may bear one or two substituentsselected from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl andC₁₋₄alkoxy); 4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R³⁰ (wherein X⁴ and X⁵ which maybe the same or different are each —O—, —S—, —SO—, —SO₂—, —NR³¹CO—,—CONR³²—, —SO₂NR³³—, —NR³⁴SO₂— or —NR³⁵—(wherein R³¹, R³², R³³, R³⁴ andR³⁵ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³⁰ represents hydrogen or C₁₋₃alkyl); 5)C₁₋₅alkylR³⁶ (wherein R³⁶ is a 5 or 6 membered saturated heterocyclicgroup with one or two heteroatoms, selected independently from O, S andN, which heterocyclic group may bear one or two substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl andC₁₋₄alkoxy); 6) (CH₂)_(q)X⁶R³⁷ (wherein q is an integer from 0 to 5, X⁶represents a direct bond, —O—, —S—, —SO—, —SO₂—, —NR³⁸CO—, —CONR³⁹—,—SO₂NR⁴⁰—, —NR⁴¹SO₂— or —NR⁴²— (wherein R³⁸, R³⁹, R⁴⁰, R⁴¹ and R⁴² eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is a phenyl group, a pyridone group or a 5 or 6 membered aromaticheterocyclic group with 1 to 3 heteroatoms selected from O, N and S,which phenyl, pyridone or aromatic heterocyclic group may carry up to 5substituents selected from hydroxy, halogeno, amino, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄hydroxyalkoxy, C₁₋₄aminoalkyl,C₁₋₄alkylamino, carboxy, cyano, —CONR⁴³R⁴⁴ and —NR⁴⁵COR⁴⁶ (wherein R⁴³,R⁴⁴, R⁴⁵ and R⁴⁶, which may be the same or different, each representshydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 7) C₂₋₆alkenylR³⁶ (whereinR³⁶ is as defined hereinbefore); 8) C₂₋₆alkynylR³⁶ (wherein R³⁶ is asdefined hereinbefore); 9) X⁷R⁴⁷ (wherein X⁷ is —SO₂—, —O— or —CONR⁴⁸R⁴⁹—(wherein R⁴⁸ and R⁴⁹, which may be the same or different, eachrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁷represents C₁₋₅alkyl which may be unsubstituted or which may besubstituted with one or more groups selected from hydroxy, fluoro andamino) with the provisos that when X⁷ is —SO₂—, X¹ is —O—, when X⁷ is—O—, X¹ is carbonyl, when X⁷ is —CONR⁴⁸R⁴⁹—, X¹ is —O— or NR¹⁸ (whereinR⁴⁸, R⁴⁹ and R¹⁸ are as defined hereinbefore); 10) C₂₋₆alkenylR³⁷(wherein R³⁷ is as defined hereinbefore); 11) C₂₋₆alkynylR³⁷ (whereinR³⁷ is as defined hereinbefore); 12) C₂₋₆alkenylX⁸R³⁷ (wherein X⁸represents —O—, —S—, —SO—, —SO₂—, —NR⁵⁰CO—, —CONR⁵¹—, —SO₂NR⁵²—,—NR⁵³SO₂— or —NR⁵⁴—(wherein R⁵⁰, R⁵¹, R⁵², R⁵³ and R⁵⁴ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is as defined hereinbefore); 13) C₂₋₆alkynylX⁹R³⁷ (wherein X⁹represents —O—, —S—, —SO—, —SO₂—, —NR⁵⁵CO—, —CONR⁵⁶—, —SO₂NR⁵⁷—,—NR⁵⁸SO₂— or —NR⁵⁹— (wherein R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸ and R⁵⁹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is as defined hereinbefore); 14) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁷ (whereinX¹⁰ represents —O—, —S—, —SO—, —SO₂—, —NR⁶⁰CO—, —CONR⁶¹—, —SO₂NR⁶²—,—NR⁶³SO₂— or —NR⁶⁴— (wherein R⁶⁰, R⁶¹, R⁶², R⁶³ and R⁶⁴ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁷ is as defined hereinbefore); 15) R³⁶ (wherein R³⁶ is as definedhereinbefore); and 16) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁶ (wherein X¹⁰ and R³⁶ areas defined hereinbefore), with the proviso that when R⁵ is bromo, R⁶ isother than unsubstituted phenyl, methyl substituted phenyl or di-halosubstituted phenyl.
 7. A pharmaceutical composition comprising acompound as claimed in any one of claims 2, 3, 4, 1 and 6 in combinationwith a pharmaceutically acceptable carrier or excipient.